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Summary: Background: Data on combination‐biologic treatment in (IBD) are still scant. Aim: To explore outcomes of patients co‐exposed to anti‐TNF and vedolizumab. Methods: Patients starting vedolizumab having measurable anti‐TNF levels after recently stopping adalimumab/infliximab (‘VDZ‐aTNF’ group), were compared with control vedolizumab patients in a retrospective 1:2 matched case‐control study. Results: Seventy‐five patients were included (25 VDZ‐aTNF, 50 VDZ). Adverse events were experienced by 9/25 VDZ‐aTNF compared to 13/50 VDZ patients (P = 0.4, follow‐up 14 weeks in all). Week 14 clinical remission was attained in 10/25 (40%) of VDZ‐aTNF patients versus 23/50 (46%) of VDZ patients (OR = 0.8, 95% CI 0.3‐2.1, P = 0.6) and clinical response in 19/25 (76%) versus 39/50 (78%) respectively (OR = 0.9, 95% CI 0.3‐2.7, P = 0.8). Corticosteroid‐free remission and corticosteroid‐free response were experienced by 30% and 54%, respectively, of the entire cohort, and were similar between the two groups. Vedolizumab drug concentrations at week 2, 6 and 14 were similar among VDZ‐aTNF and VDZ patients (P > 0.5). Multi‐variable analysis showed independent association of some vedolizumab drug‐levels time‐points with baseline albumin and weight, but not with anti‐TNF co‐exposure. In a prospective study of a separate cohort of patients starting infliximab (n = 12), the percentage of α4β7+ memory T cells, slightly but nonsignificantly increased throughout weeks 0, 2 to 14 (26 ± 2.3%, 27.8 ± 2.9%, 29.5 ± 2.6% respectively, P = 0.06). Conclusions: Vedolizumab/anti‐TNF co‐exposure did not generate new safety signals during 14‐weeks induction, nor did it reduce efficacy or alter vedolizumab pharmacokinetics. These observations may aid the design of future co‐biologics trials and also suggest that a deliberate waiting‐interval between anti‐TNF cessation and subsequent vedolizumab initiation may not be warranted. [ABSTRACT FROM AUTHOR]

Background Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. Aim To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. Methods A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab ( ATI) levels were measured by our previously described drug-tolerant ELISA assay. Results Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 μg/mL vs 13.5, 9.5 μg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 μg/mL-eq vs 3.8, 4.4 μg/mL-eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 μg/mL ( AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 μg/mL-eq ( AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. Conclusions Infliximab levels below 6.8 μg/mL and antibodies to infliximab levels above 4.3 μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients. [ABSTRACT FROM AUTHOR]

Background Anti-adalimumab antibodies ( AAA) are associated with loss of clinical response ( LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. Aim To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. Methods The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as 'sero-reversal', elevation of drug levels and regained clinical response were the sought outcomes. Results Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. Conclusions In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies. [ABSTRACT FROM AUTHOR]

Background Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis ( UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce. Aim To compare infliximab trough and anti-infliximab antibody levels at a standard fixed time-point during induction between patients with acute severe and moderately severe UC. Methods A multi-centre retrospective study comparing infliximab drug and antibody levels 14 days after the first infusion in hospitalised acute severe UC versus out-patients with moderately severe UC was performed. Results Sixteen acute severe UC patients, hospitalised between 2010-2015 and refractory to intravenous corticosteroids, were treated with infliximab 5 mg/kg salvage therapy. They were compared to 16 moderately severe UC out-patient controls. Mean infliximab trough levels at day 14 were significantly lower in patients with acute severe UC compared to moderately severe UC (7.15 ± 5.3 vs. 14.4 ± 11.2 μg/mL, P = 0.007). Seven patients (three acute severe and four moderate severe UC) were primary nonresponders to infliximab induction therapy. Infliximab level at day 14 did not differ between responders and nonresponders (9.8 ± 9 vs. 12.1 ± 10.6 μg/mL, respectively, P = N.S.). However, week 2 median antibody-to-infliximab levels were numerically higher among primary nonresponders (3.4 ± 5.7 vs. 1.2 ± 4 μg/mL-eq, respectively, P = 0.06). Conclusions Infliximab trough levels at day 14 were lower in patients with acute severe UC compared to moderately severe UC, possibly due to a higher inflammatory burden and/or increased drug clearance. However, drug levels at day 14 were not lower among nonresponders compared with responders. Controlled trials are warranted to examine whether an a-priori-intensified infliximab induction protocol will lead to an improved outcome in acute severe UC. [ABSTRACT FROM AUTHOR]

Background Low drug levels are associated with emerging loss of response to anti-TNF. However, this may not be the case in patients with long-term remission. Aim To investigate the outcome of anti-TNF discontinuation in patients with long-term remission and incidental undetectable drug levels. Methods A retrospective cohort study examining the duration of relapse-free survival in IBD patients in remission who discontinued infliximab or adalimumab having undetectable drug levels. Results Forty eight patients who discontinued anti-TNF while in remission and had available drug levels were identified in two centres in France and Israel (infliximab-treated 35, adalimumab-13, Crohn's disease 30, ulcerative colitis 18, mean treatment duration of 22.7 ± 12.4 months). Endoscopy/MRE before stopping showed absence of active inflammation in 40/42 (95%) of evaluated patients, while inflammatory biomarkers (CRP and/or Calprotectin) were completely normal in only 31/ 48 (65%) of patients. During 12 months median follow-up, relapse occurred in 16/ 20 (80%) of patients who stopped anti-TNF while having measurable drug levels compared with 9/28 (32%) of patients who had undetectable drug levels (OR: 8.4, 95% CI: 2.2-32, P = 0.002). Relapse-free survival after anti-TNF cessation was significantly longer in patients with absent drug compared to those with detectable drug (P < 0.001, log rank test). On multivariate analysis, a patient's decision to stop therapy was weakly associated and abnormal inflammatory biomarkers and detectable drug levels were both strongly and independently associated with a higher risk of relapse after drug discontinuation. Conclusion Incidental finding of undetectable anti-TNF drug levels in patients with stable long-term deep remission may identify a subset of patients whose clinical remission is no longer dependent on anti-TNF treatment. [ABSTRACT FROM AUTHOR]

Background Varicella zoster virus ( VZV) is a severe and preventable infection in immunosuppressed IBD patients. ECCO guidelines recommend VZV immunisation in patients with negative VZV exposure history. The value of patient-reported VZV exposure history for prediction of seropositivity in IBD patients remains unknown. Moreover, data on VZV immunity in adult IBD patients or accuracy of VZV serological testing under immunomodulator treatment is sparse. Aims The primary aim was to determine the prevalence of seropositivity for VZV- IgG in immunomodulator-treated IBD patients. A secondary aim was to establish the value of patient-reported history of past VZV infection for prediction of immunity, to validate the current vaccination strategy. Methods History of VZV-related illness was accessed by epidemiological questionnaire, and serological testing for VZV- IgG was performed. Serum anti- TNF medications levels were measured when applicable. Results One hundred twenty one IBD (86% Crohn's disease, mean age 37 ± 12.8) patients were included in the study. Immunomodulator therapy was received by 87% (anti- TNFs- 71%) of the patients. Previous exposure to VZV was reported by 104 patients, and 97/104 (93%) were VZV- IgG seropositive. Seventeen patients, all seropositive, reported negative exposure history. The calculated positive and negative predictive values for the reported history of VZV exposure were 93% and 0% respectively. Conclusions Negative history of VZV exposure is a poor predictor of seronegativity. History-positive patients may still be seronegative and exposed to VZV infection. We suggest serological testing of all IBD patients with subsequent immunisation of the seronegative patients before initiation of immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Summary Background Anti-drug antibodies can be elicited by infliximab and adalimumab, but the rate of their decay after therapy is stopped is unknown. Aim To investigate the decline of anti-drug antibody titre after anti- TNF cessation, and to evaluate the clinical utility of anti-drug antibody measurement before anti- TNF re-induction. Methods Inflammatory bowel disease ( IBD) patients who stopped anti- TNF therapy and had measurable anti-drug antibodies were prospectively followed up by serial blood measurements of antibodies levels. The clinical outcome of a second cohort of patients who received re-induction by infliximab or adalimumab after a drug holiday >4 months was determined vis-à-vis their anti-drug antibodies status before re-induction. Results The first cohort included 22 patients with anti-drug antibodies who were prospectively followed up after cessation of anti- TNF. Sixteen had antibodies-to-infliximab ( ATI) and six had antibodies-to-adalimumab ( ATA). ATI titres declined within 12 months to below detection levels in 13/16 infliximab-treated patients, whereas ATA titres became undetectable in only 2/6 adalimumab-treated patients ( P = 0.04). The second cohort comprised 27 patients who resumed anti- TNFs (24 infliximab, 3 adalimumab). Of these, 3/5 patients with measurable anti-drug antibodies before re-induction experienced severe hypersensitivity reaction and/or nonresponse mandating drug-discontinuation, compared to 11/22 patients who were re-induced without measurable anti-drug antibodies ( OR = 1.5, 95% CI 0.2-11, P = 0.7). Conclusions Antibodies to infliximab titres decline to undetectable levels within one year of cessation of infliximab in the majority of patients, whereas antibodies to adalimumab seem to persist longer after adalimumab discontinuation. Measuring antibodies to infliximab prior to infliximab re-induction is probably of little clinical utility, especially if more than a 12-month drug-holiday has elapsed. [ABSTRACT FROM AUTHOR]

Background Rectally administered mesalazine (mesalamine; 5-aminosalicylic acid) is the first-line therapy for treatment of distal ulcerative colitis. Recently, a high-volume 5-aminosalicylic acid foam has been shown to be as effective and safe as standard 5-aminosalicylic acid enema. Aim To study the efficacy and safety of a low-volume vs. a high-volume 5-aminosalicylic acid foam. Methods In this investigator-blinded study, patients with active distal ulcerative colitis [Clinical Activity Index (CAI) > 4, Endoscopic Index ≥ 4] were randomized to receive 2 × 1 g/30 mL low-volume ( n = 163) or 2 × 1 g/60 mL high-volume 5-aminosalicylic acid foam ( n = 167) for 42 days. Primary end point was clinical remission (CAI ≤ 4) at the final/withdrawal visit (per-protocol). Results 330 patients were evaluable for efficacy and safety by intention-to-treat, 290 for per-protocol analysis. Clinical remission rates at week 6 (per-protocol) were 77% on low-volume foam vs. 77% on high-volume foam ( P = 0.00002 for non-inferiority). The low-volume foam was associated with a lower frequency of severe discomfort, pain and retention problems. Conclusions Low-volume 5-aminosalicylic acid foam is as effective and safe as a high-volume 5-aminosalicylic acid foam in the treatment of active distal ulcerative colitis, but offers compliance advantages compared to the high-volume preparation. [ABSTRACT FROM AUTHOR]

Background: Gastro-oesophageal reflux disease is a common entity. Erosive oesophagitis, ulcers and Barrett's oesophagus, which is found in up to 10% of gastro-oesophageal reflux disease patients, characterize severe gastro-oesophageal reflux disease. Patients with Barrett's oesophagus have 0.5% per patient-year risk of developing oesophageal adenocarcinoma. Currently, it appears that a minority of those at risk for Barrett's oesophagus undergo screening in part because of the costs associated with endoscopy as well as risks of sedation. A new ingestible PillCam oesophageal capsule developed may offer an alternative office-based approach to visualize the oesophagus without sedation. Aim: To compare the oesophageal capsule to conventional upper endoscopy for detection of oesophageal pathologies. Methods: A newly developed capsule, which acquires video images from both ends of the device at a 4 frame/s rate, was ingested by 17 fasting patients with suspected oesophageal disorders. An ingestion procedure aimed to lengthen capsule transit time in the oesophagus was utilized. Subsequently, a standard upper endoscopy was carried out. The investigator interpreting the capsule findings was blinded to the endoscopy results and vice versa. Patients with dysphagia, known Zenker's diverticulum, intestinal obstruction, cardiac pacemaker or pregnancy were excluded. Results: Twelve of the 17 patients examined had oesophageal findings using the endoscope as the gold standard. Capsule endoscopy identified oesophageal pathology in all 12 of these patients and an additional pathology in one patient that was missed during endoscopy. For the purpose of this study, this finding was regarded as a false-positive. The mean oesophageal passage time was 189 ± 280 s. The positive predictive value of the oesophageal capsule for any oesophageal pathology was 92% and the negative predictive value was 100%. Oesophageal capsule sensitivity was 100% and specificity 80%. There were neither swallowing difficulties nor complications subsequent to ingestion in any subjects. Seventy-three percentage of patients preferred the oesophageal capsule procedure on conventional endoscopy. Only one patient preferred oesophagogastroduodenoscopy. Conclusions: This pilot study has shown that oesophageal capsule endoscopy is an accurate, convenient, safe and well-tolerated method to screen patients for significant oesophageal disorders. No sedation is required, which may allow simple, office-based screening and assessment. Further, large-scale studies are necessary to more fully assess this novel diagnostic tool. [ABSTRACT FROM AUTHOR]

Background: There are few reports which the tests used for diagnosing Helicobacter pylori infection and monitoring its eradication in children.Study Aims: Prospective evaluation of invasive (gastric histology, rapid urease test [RUT]) and non-invasive (stool antigen [FemtoLab H. pylori], urea breath test [UBT]) tests in the diagnosis of H. pylori infection and post-treatment eradication in children and adolescents.Methods: Ninety-two patients (50 male, 42 female) referred for upper gastrointestinal endoscopy were prospectively enrolled. UBT was performed and stool specimens collected for monoclonal enzyme immunoassay for H. pylori antigen (FemtoLab) 1 to 4 days before endoscopy. H. pylori in gastric biopsies was evaluated by RUT and staining with hematoxylin-eosin and giemsa. Eradication therapy was given to children with abdominal pain and H. pylori gastritis. FemtoLab H. pylori and UBT were repeated 6 weeks after the end of triple therapy.Results: Histology identified H. pylori in 49 of 92 (53%) subjects. Concordance between histology and RUT was found in 78 of 92 children. FemtoLab H. pylori was positive in 41 of 78 (52.6%) children with sensitivity, specificity, positive and negative predictive values of 97.5%, 94.7%, 95.1% and 97.3%, respectively. For UBT, these values were 100%, 96.9%, 97.5% and 100%, respectively. Twenty-six of 36 patients who received triple therapy returned for eradication evaluation. Tests for H. pylori antigen in stool were positive in 10 of 26 and for UBT in 11 of 26.Conclusion: Stool antigen (FemtoLab) and UBT were equally effective in diagnosing and confirming eradication of H. pylori infection in children. [ABSTRACT FROM AUTHOR]

Our recent identification of chondroitin sulphate E-containing mast calls (E-MC) in the human colonic mucosa is extended here to the human gastric mucosa by using a combination of both biochemical and immunochemical approaches. Most of the mast cells in human gastric biopsies, which were located mainly around small blood vessels in the submucosa, showed various degrees of degranulation and were granular when stained by monoclonal antibody against chondroitin sulphate proteoglycan. The human gastric mucosa biopsies incorporated (35S)-sulphate into proteoglycans. Cells in the tissues which were histamine-positive also incorporated (35S). The 35S proteoglycans, which were either left associated with the tissue or released into the medium, were found not to be heparin but chondroitin sulphate E. Incubation of the human gastric mucosa biopsies in the presence of anti-human IgE revealed significant enhancement in the release of both (35S)-chondroitin sulphate E proteoglycan and histamine. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the management guidelines for the treatment of patients with inflammatory bowel disease (IBD) and its conflict of interest.

Background: Curcumin and QingDai (QD, Indigo) have been shown to be effective for treating active ulcerative colitis (UC)., Aim: To evaluate the real-world experience with the Curcumin-QingDai (CurQD) herbal combination to induce remission in active UC., Methods: A retrospec-tive multicentre adult cohort study from five tertiary academic centres (2018-2022). Active UC was defined as a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3. Patients were induced by CurQD. The primary outcome was clinical remission at weeks 8-12, defined as SCCAI ≤2 and a decrease ≥3 points from baseline. Secondary outcomes were clinical response (SCCAI decrease ≥3 points), corticosteroid-free remission, faecal calprotectin (FC) response (reduction ≥50%), FC normalisation (FC ≤100 μg/g for patients with FC ≥300 μg/g at baseline), and safety. All outcomes were analysed for patients who were maintaining stable treatment., Results: Eighty-eight patients were included; 50% were biologics/small molecules experienced, and 36.5% received ≥2 biologics/small molecules. Clinical remission was achieved in 41 (46.5%), and clinical response in 53 (60.2%). Median SCCAI decreased from 7 (IQR:5-9) to 2 (IQR:1-3); p < 0.0001. Of the 26 patients on corticosteroids at baseline, seven achieved corticosteroid-free remission. Among 43 biologics/small molecules experienced patients, clinical remission was achieved in 39.5% and clinical response in 58.1%. FC normalisation and response were achieved in 17/29 and 27/33, respectively. Median FC decreased from 1000 μg/g (IQR:392-2772) at baseline to 75 μg/g (IQR:12-136) at the end of inductions (n = 30 patients with paired samples); p < 0.0001. No overt safety signals emerged., Conclusion: In this real-world cohort, CurQD effectively induced clinical and biomarker remission in patients with active UC, including patients who were biologics/small molecules experienced., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)